There are data documenting that pretreatment with lithium (Li) maximizes the uptake and residence time of radioactive iodine (RAI) in the metastatic differentiated thyroid cancer (DTC) lesions, without the established effect on the outcome. The goal of our study was to compare the efficacy of the three methods of preparation for dosimetry-based RAI therapy of metastatic DTC: recombinant human TSH (rhTSH), thyroid hormone withdrawal (THW), THW with pre-treatment with Lithium for 7 days (THW+Li). We performed a retrospective analysis of metastatic DTC patients treated with dosimetry-based RAI, divided into 3 groups: rhTSH, THW and THW+Li. The primary outcome was overall survival (OS) and progression free survival (PFS). Kaplan-Meier survival analyses were performed to compare time to progression and death between the groups. Cox proportional hazards regression model was performed to study the contribution of age, TNM status and location of distant metastases. The study cohort consisted of 135 patients (82 women, 53 men) treated with average cumulative RAI activity of 550+/-393 mCi and prepared for RAI with rhTSH (n=42), THW (n=52) and THW+Li (n=41). During the follow up of 7.1+/-7.6 years, 49.6% of patients (67/135) had disease progression and 11.8% of patients (n=16/135) died. We documented that pretreatment with Lithium was associated with improved OS in patients with metastatic DTC, but the contribution of age and presence of widespread disease with metastases to the brain and spine were more important factors associated with decreased OS and PFS.